Project Summary Despite enormous progress in blood cancer research, the ability to treat and prevent multiple myeloma, the second most common hematologic cancer in the United States, remains severely limited. This is particularly true for the subset of patients diagnosed with high-risk myeloma. Addressing the current limitations will require additional research efforts, including projects on the biological significance of recently discovered candidate high-risk myeloma drivers, such as the forkhead box M1 transcription factor, FOXM1. The long-term goal of this research program is to improve the outcome of myeloma and related plasma cell neoplasms. The main objective of the specific research project proposed here is to elucidate the mechanism by which FOXM1 enhances the aggressiveness of myeloma. The central hypothesis is that FOXM1 drives and affords a promising treatment opportunity for high-risk myeloma. Two specific Research Aims have been designed to test this hypothesis and achieve the objective of this application. The studies in Aim 1 will employ human myeloma cell lines and patient-derived myeloma cells to assess the role of FOXM1 in myeloma biology (e.g., clonogenic growth and survival) and myeloma genetics (e.g., FOXM1 target genes and drug sensitivity). The experimental strategy includes the inducible up or down regulation of FOXM1 in myeloma cells, ChIP-seq analysis of the FOXM1-governed gene network, and the determination of FOXM1 levels in myeloma cells in the course of disease progression. The studies in Aim 2 will determine whether FOXM1 drives neoplastic plasma cell development in a genetically engineered mouse model of human myeloma. An additional objective concerns the correlation of FOXM1 status of myeloma-like tumors in mice with the response to small-molecule FOXM1 and proteasome inhibitors. The experimental strategy includes the adoptive transfer of genetically tagged B-lymphocytes that express elevated levels of human FOXM1. Also included are preclinical treatment studies in which the response of myeloma-like tumors to proteasome inhibition will be assessed. Supported by strong preliminary results that provide a sound rationale for this application, the proposed research is poised to facilitate novel targeted approaches to the therapy of high-risk multiple myeloma.